Therapeutic agent for improving cardiovascular function

ABSTRACT

Methods of and compositions for a therapeutic agent for improving cardiovascular function utilizing as the active agent a compound represented by the formula   WHEREIN R1 is hydrogen or acetyl; R2 is hydrogen, bromine or chlorine, AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, ARE DISCLOSED.

United States Patent Pressman et al.

[ Mar. 25, 1975 I "THERAPEUTIC AGENT FOR IMPROVING OTHER PUBLICATIONS CARU|0VASCULAR FUNCTION Stempcl Chem. Abst Vol. 75 (1971) page [75] Inventors: Berton Charles Pressman, Coral I |7|49V- Gables; Norberto Tumali de Pr ma y Examiner-Sam Rosen Guzman, Miami Beach, both of Fla. Attorney, Agent, or Firm-Samuel L. Welt; Jon S. [73] Assignee: University of Miami Saxe; Gerald Rosen 22 F] d: A 6, 1973 1 pr [57 ABSTRACT [21] Appl. No: 348,809

Methods of and compositions for a therapeutic agent for improving cardiovascular function utilizing its the [52] U.S. Cl. 424/283 active agent a compound represented by the formula 'cn COQH CH CH 0H CH3 R2 OH 0 CH3 {,51] Int. Cl A6lk 21/00 wherein R is hydrogen or acetyl; R is hydrogen, [58 Field of Search 424/283 bromine or chlorine,

' I 1 w h References Cited grisciltohsiiharmaceutically acceptable salts t ereof, are

UNITED STATES PATENTS 3,715,372 2/1973 Stempel et a1 424/283 10 Claims, N0 Drawmgs Massachusetts. Lyophilized tubes of the culture bear- 1 2 A THERAPEUTIC AGENT FOR IMPROVING wherein R is hydrogen or acetyl; R is hydrogen, bro- CARDIOVASCULAR FUNCTION mine or chlorine,

DESCRIPTION OF THE INVENTION and the pharmaceutically acceptable salts thereof. Representative of the active compounds useful m this The lnvention described herein was made in the 5 invention are course of work under a grant or award from the De- 3- thyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6- partment of Health, Education, and Welfar 7-[5-ethyl-3-methyl-5(5-ethyl5-hydroxy-6-methyl-2-' Antibiotic X-537A and various derivatives of antlbih d 2 h d f ]lh t n li lj otic X-537 A are known to possess coccidiostatic and acid (Crystalline antibiotic X 537A); antibacterial properties. Wehave discovered that antil0 br0m0 3 methy| 6 {7 ethyl 4 hydmxy 3,5 El i E of F ij P 5 1 dimethyl-6-oxo-7[5-ethyl-3-methyl-5-(5-ethyl5- g'i e 3 3 gamma F hydroxy-o-methyl-Z-tctrahydropyranyl)'2- f .lscovgre e compoun 5 Cause tetrahydrofuryl]heptyl}salicylic acid, sodium salt; dial stimulation.

. 3-methyl-6-{7-ethyl-4-hydroxy-3,5-dlmethyl-o-oxo- Antibiotic X-537A a designation given to a crystall5 7-[5-ethyl-3-methyl-5-(S-ethyl-S-hydroxy-6-methyl-2- line antibiotic produced by a Streptomyces organism I I isolated from a sample of soil collected at Hyde Park tetrahydropymnyl)'2'letmhydmfuryllheptyudcetyl salicylic acid, sodium salt;

5-chloro-3-methyl-6-{7-ethyl-4-hydroxy"3,5-

in the labo ato desi nat'o X-537 re d os't d g r W g In we ep 16 dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5- with the United States Department of Agriculture, Ag- 20 riculture Research Service, Northern Utilization Ret y e e search and Development Division, Peoria, Ill. The cultetrahydrofury}lheptynsaheyllc F I ture given id tifi ti number NRRL 33 by the The most significant desired criteria for chemical i h m Research service has been made} avail compounds used to treat chronic heart conditions,such able to the public through NRRL. The culture is also as Congestive heart failure, or emergency heart Condiavailable to the public from the International Center of tions -Ew Shock heart failure, are that The Compound I f ti i ll b i i h W H,(), i B l i should have a positive inotropic effect with little or no The antibiotic material, heretofore identified as anti- ChFOHOtTOPiC effects and sp ay minimal, if y. adrenbiotic X-537A, upon laboratory analysis has been ergic action. Other desirable criteria are that the comfound to be 3-methyl-6-{7-ethyl-4-hydroxy-3,5- pounds have a rapid onset of action, require a small efdimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5- fective dose, are non-toxic at the effective doses, dishydroxy-6-methyl-2-tetrahydropyranyl)-2- play a satisfactory duration of action, display a return tetrahydrofuryllheptyll-salicylic acid, i.e., a compoun to the original pre-drug values of cardiovascular ZICIlV- represented by the formul r V V I ity, and continued identical responses to subsequently COOH CH3 OH Antibiotic X-537A is prepared by growing the Streprepeated identical doses. lt is also desirable that such tomyces organism in an aerated submerged culture, compounds be amenable to oral or parenteral adminis- With the pH 0f the br th adjus d F0 about e tration. The oral administration is particularly preabout 6.5 to -5- The ed um l e COIltamS nltfO ferred for long term treatment of chronic diseases, e.g. gen Source Such as Yeast, y derlved Product, 9 congestive heart failure, while parenteral administrameivlb bean meal and the llke, Wlth Soybean meal bemg tion is the choice for emergency treatment, e.g., shock, the most preferred; and a carbohydrate source, such as acute heart faglum sugar, molasses and the like, ,with brown sugar being most preferred. The fermentation is carried out at slightly elevated temperatures, i.e., between about 25C. and 35C., with the preferred incubation temperature being about 28C. After an incubation of about The active compounds of this invention fulfill the desired criteria and are thus useful for stimulation of cardiovascular functions and treating such ailments as cardiogenic shock, septic shock and congestive heart fail- 4 to 6 days, the fermentation broth is filtered and the antibiotic recovered by extraction. The active compounds useful in this invention form The active compounds ofthis invention include those a variety of pharmaceutically acceptable salts. These represented y the formula salts are prepared from the free acid by methods well coon CH3 CH3 R2 0 CH3 known in the art, for example, by washing the free acid in solution with a suitable base or salt. Examples of such pharmaceutically acceptable basic substances capable of forming salts for the purpose of the present invention include alkali metal bases, such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkaline earth metal bases, such as calcium hydroxide, barium hydroxide and the like; and ammo nium hydroxide. Alkali metal or alkaline earth metal salts suitable for forming pharmaceutically acceptable salts can include anions such as carbonates, bicarbonate and sulfates. Preferred for use in this invention are salts formed from alkali metal bases.

The specific compounds useful in this invention are known compounds and their preparation is disclosed in US. Pat. No. 3,715,372.

Thus, compounds wherein R is acetyl can be prepared from compounds wherein R is hydrogen by using conventional acetylating agents such as acetic anhydride or acetyl chloride.

Compounds wherein R is chlorine or bromine can be prepared from compounds in which R is hydrogen by any conveniently available halogenating technique, e.g., bromination with bromine or chlorination with chlorine.

For use as cardiovascular agents, the active agents are formulated, using conventional inert pharmaceutical adjuvantmaterials, into dosage forms which are suitable for oral or parenteral administration. Such dosage forms include tablets, suspensions, solutions, hard or soft capsules, dragees and the like. The identity of the inert adjuvant materials which are used in formulating the active compounds into oral and parenteral dosage forms will be immediately apparent to persons skilled in the art. These adjuvant materials, either inorganic or organic in nature, include, for example, water, dimethylsulfoxide, gelatin albumin, lactose, starch, magnesium stearate, preservatives, stabilizers, wetting agents, emulsifying agents, salts for altering osmotic pressure, buffers, etc. which can be incorporated, if desired, into such formulations.

The quantity of active agent which is present in any of the above described dosage forms generally varies from to 25 mg. per unit dosage. The dosage administered to a particular patient is variable, depending upon the clinicians judgment using as the criteria the condition and size of the patient, the potency of the active agent and the patients response thereto. An effective dosage amount of active agent can therefore only be determined by the clinician utilizinghis best judgment on the patients behalf. 4

Generally, parenteral doses should be from about mg. to about 50 mg. for the average size man. Smaller persons or larger persons require adjustments due to size. Oral doses, usually capsules, but tablets can be used, generally are about twice the parenteral dose.

The frequency of the dose would depend upon the patients condition. Chronically ill patients may require administration every 2 to 3 hours or once a day, depending on the severity of the disease and the patients response. '7 H Emergency patients frequently need only one dose of active compound p ar ticularly those in shock.

The cardiovascular effects of the agents are manifested by positive inotropic effects with minimal chronotropic effects. For example, normal female mongrel dogs, weighing 30-35 lbs. were anesthetized with intravenous sodium pentobarbitol (2O mg./kg.) and artificially ventilated. Catheters were introduced through the femoral vessels to the left ventricular cavity, thoracic aorta and inferior vena cava for left ventricular and aortic pressures, and drug administration, respectively.

The derivative of the left ventricular pressure was obtained separately from a Statham micromanometcrtipped catheter. The derivative of pressure. dP/dt, was provided by an appropriate R-C differentiating circuit. The His bundle electrogram was obtained from a bipolar catheter positioned towards the medial cusp of the tricuspid valve. A Walton-Brodie strain gauge was sutured at the mid-portion of the right ventricular myocardium for recording the isometric ventricular segmental tension. This function was tranformed to its derivative (dT/dt) by an R-C differentiator. Cardiac output was obtained by the conventional dye dilution technique. The electrocardiogram was monitored from standard leads attached to the extremities of the dog. All parameters were recorded simultaneously and continuously by a multichannel photographic recorder.

The electrophysiological and hemodynamic responses of the dogs were measured at a time before, and at various time intervals after, an intravenous injection of 20 umoles of 3'methyl-6 {7-ethyl-4-hydroxy- 3,5-dimethyl-6-oxo-7-[ 5-ethyl-3-methyl5( 5-ethyl-5- hydroxy-6-methyl-2-tetrahydropyranyl)-2- tetrahydrofu ryl]heptyl}salicylic acid (0.62 mg.kg.) administered as a 10" M solution in dimethylsulfoxide.

The results are shown for a representative dog in the following Table:

Example 8 Tablet Formulation heptyl salicylic acid Lactose I 13.5 mg.

Corn Starch 55.5 mg.

Pregelatinized Corn Starch 8 mg.

Calcium Stearate 3 .mg. 205 mg.

26%, and pulse pressure increased 28% The onset of action of the active agent was rapid with a smooth continuous progression until maximum response in about 10-15 minutes. The effect lasted about 2 hours by which time the effects diminished until the monitored cardiovascular parameters returned to pre-drug values. Fresh doses thereafter elicited the same responses in the same dogs.

In contrast, no significant changes were observed in heart rate, atrio-His bundle, and His-bundle Purkinje nal of the R wave of lead 11. Femoral artery blood pressure was measured with a Statham pressure transducer. All drugs were dissolved in saline (0.9%) and administered rapidly as a single injection through a polyethylene catheter into the left femoral vein. Monitored parameters were recorded on two separate 2- channel Sanborn direct writing recorders.

The test compounds were evaluated for effects on heart rate, contractile force and mean arterial blood pressure. The results are set forth in the following Table.

Table ll Maximal Maximal Effective lnotropie Heart Mean Dose Time Responses Rate B.P. (mg/kg.) Post-Drug ('/1 Change/ (91 Change/ 4 Change] i.v. (min) Control Control) Control 3 11l01li)'l-6-{7( R )-ethyll( S J-hydroxy- R 5(S )-dimctltyLb-oxo-ll 5(5 )-ethyl- 3( S niethvl-5( 5(R )-ethyl-5-hydroxv-6(S) methyllt R )tetrahydropyru'nyl )-Z( 5 tetrithj'drofurylIheptylhalicylic acid 1.0 +64 +22 +32 5-cliloro-3-methyl-(i-{7-ethyl-4-hydroxy 3,5-dimetliyl-b-oxo-7-[5-ethyl-3-mcthyl- 5-(5-etliyl5 hydrox '-6methyl-2- tetruhvdropyranyl )-2-tetrnh vdrofu ryl] heptyl j sulicylic acid 2.0 +19 4 Z 3-methyLb-{7-ethyl4 hytlroxy-3,5- dimethyl-(i-oxo- 7-I 5-ethyl-3-niethyl-5-( 5 ethyl-5-h 'droxy--methyl-Z-tetrahy(lropyranvl )-2tetrahydrofur vl Iheptyl acetyl}salieylie acid 1.0 l5 +28 3 7 S-bromo-3-methyl-6-{7-ethyl-4-hydroxy- 3,5tlimethyl-b-oxoJl 5-ethyl-3-methyl-5- tS-eth '1-5-hydroxy-b-methyl-Ltetrahydropyranyl )-Z-tetrahydroluryl lheptyli'sulicylie acid 4.0 +88 0 +57 5-chloro-3-methyl-6- {7-ethyl-4-hydroxy-3,5- dimethyl-6-oxo-7-[5ethyl-3-methyl-5-(S-ethyl-S- hydroxy-6methyl-2-tetrahydropyranyl)-2- tetrahydrofuryl]heptyl}salicylic acid;

3-methyl-6-{7(R)-ethyl-4-(S)-hydroxy-3(R)- dimethyl-6-oxo-7-[5(S)-ethyl-3(S)-methyl-5(5(R)- ethyl-5-hydroxy-6(S)-methyl-2(R)- tetrahydropyranyl)-2(S)-tetrahydrofuryl]heptyl}salicylic acid; and

5-bromo-3-methyl-6-{7-ethyl-4-hydroxy-3,5- dimethyl-6-oxo-7[5-ethyl-3-methyl-5-(S-ethyl-S- hydroxy-6-methyl-2-tetrahydropyranyl)-2- tetrahydrofuryHheptyl} salicylic acid in the form of their sodium salts were subjected to the following test in anesthetized dogs: I a

Four mongrel dogs of either sex, weighing 7 to 12 kg., were anesthetized with intravenously administered thiopental sodium (15 mg./kg.) and barbital sodium (275 mg./kg.). Each test dog was used as its own control. Each of the four test dogs received one drug.

During surgical manipulations, artifical respiration was maintained by intubation using a Bird respirator (Mark 8). Myocardial force of contraction was measured by opening the chest through the left 4th interspace and suturing a strain gauge arch to the surface of the right ventricle. The chest was then closed by suturing, pneumothorax was reduced, and spontaneous breathing permitted. Electrocardiograms were recorded using lead '1 1. Heart rates were recorded on a S nb ar qtasbqmst rby isin the dec iwlsis:

The compounds are non-toxic within the effective dose range as evidenced by the LD expressed in mg./kg. in animals. Thus, by oral administration the LD of antibiotic X-537A is 40 mg./kg. in rabbits. 122 mgjkg. in rats and 146 mg./kg. in mice.

The following examples illustrate the invention.

submerged culture in shaken flasks. The pH of the broth was adjusted by the addition of KOH solution to 6.5-7.5, then the broth was sterilized. A tank fermentation was used wherein a 510% inoculum consisting of 3 day old submerged growth from aerated bottles was used in the tank. The medium contained 2% soybean flour, 2% brown sugar, 0.5 K HPO The fermentation was carried out at 28C., under positive air pressure, with air-flows of 5-10 cu. ft. of air per minute per 40 to gallon liquid charge. The broth was harvested after 4 to 6 days fermentation, filtered, and the antibiotic was recovered by extraction. The extraction was carried out as follows:

204 Liters of broth were filtered and the wet filter cake was suspended in liters of butyl acetate and mixture was stirred overnight, at room temperature.

ness in vacuo, the crystalline residue suspended in petroleum ether and filtered, yielding 24.49 g. of a mixture of the salt and free acid form of 3-methyl-6-{7- ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3- methyl-5-(5-ethyl-5-hydroxy-6-methyl-2- tetrahydropyranyl-2-tetrahydrofuryl]heptyl}salicylic acid. The mother liquor of the solid yielded an additional 5.73 grams of the antibiotic.

After recrystallization from ether-petroleum ether, this material, which contained sodium was dissolved in ether and washed with dilute sulfuric acid to convert it to the free acid. Removal of the ether left an oily residue which crystallized from ethanol to yield pure 3- methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5- ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2- tetrahydropyranyl)-2-tetrahydrofuryllheptyl salicylic acid. Several recrystallizations from ethanol did not change the melting point which remained unsharp at l00l09C.

EXAMPLE 2 5-bromo-3-methyl-6-{7-ethyl-4-hydrox y-3,5-dimethyl- To a solution of 1.53 g. of the sodium salt of antibiotic X-537A in 30 ml. carbon disulfide was added dropwise a solution of 0. 14 ml. bromine ml. carbon disulfide at -5 over 10 minutes. The solvent was removed under a stream of nitrogen at room temperature (approximately 2 hours); The residue was purified by dissolving it in ethyl acetate and the solution Washed successively with aqueous sodium bisulfite and sodium carbonate. After drying (Na SO the solution was evaporated under reduced-pressure and the residue crystallized from ethyl acetate to give 5-bromo-3- methyl-6- ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-l5- ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2- tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}salicylic acid, sodium salt as colorless cubes, m.p. 185, [01],, 7.36 1% in methanol).

EXAMPLE 3 3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7- dium carbonate solution, dried (Na SO and evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride and the solution evaporated on the steam bath with additions of hexane until crystallization started. Cooling to 0, gave 3- methyl-6{7-ethyl-4-hydroxy-3,5-dimethyl-6oxo7-[5 ethyl-3-methyl-5-(5-ethyl-5-hydroxy'6-methyl-2- tetrahydropyranyl)-2-tetrahydrofuryllheptyl}acetyl salicylic acid, sodium salt white needles, mp. l86-l87, [11],, l8.75 (1%, CH OH).

EXAMPLE 4 Sodium Salt of Antibiotic X-537A The sodium salt was prepared by shaking an ether so- 7 EXAMPLE 5 5-chloro-3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl- 6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6- methyl-Z-tetrahydropyranyl )-2-tetrahydropyranyl )-2- tetrahydrofuryl1heptyl} salicylic acid To a cold solution (-3) of 6.12 g. of the sodium salt of antibiotic X-537A in 50 ml. of chloroform/3 ml. of carbon tetrachloride was slowly added 34 ml. of carbon tetrachloride saturated with 10 millimoles of chlorine gas. The reaction was continued for one-half hour after which the solution was filtered and the filtrate treated with a saturated aqueous solution of Na CO The solvent layer was dried over Na SO and concentrated to a small volume from which after addition ofhexane the crystalline product was recovered. The crystalline material which had a tendency to incorporate the solvent of crystallization was twice recrystallized from methylene chloride/ether and acetone/hexane; mp.

EXAMPLE 6 A 5 ml. parenteral solution was prepared utilizing the following ingredients:

Example 6 A 5 ml. parenteral solution was prepared utilizing the following ingredients:

per ml.

Antibiotic X-537A 5.l mg. Propylene glycol 0.5 ml. Anhydrous ethanol 0.1 ml. Benzyl alcohol 0.015 ml.

Water for injection q.s. to 1.0 ml.

Example 7 Tablet Formulation Per Procedure:

I. The drug was mixed with the lactose, corn starch and magnesium stearate in a suitable mixer.

2. The mixture was further blended by passing through a Fitzpatrick Comminuting machine fitted with a No. lA screen with knives forward.

3. The mixed powders were slugged on a tablet compressing machine.

4. The slugs were comminuted to a mesh size (No. 16 screen) and mixed well.

5. The tablets were compressed at a tablet weight of 100 mg. using tablet punches having a diameter of approximately inch. (Tablets may be either flat or biconvex and may be scored if desired.)

3-Methyl6-{7(R)-ethyl-4(S)-hydroxy-3(R),5(S)- dimethyl-6-oxo-7-[5(S)-ethyl-3(S)-methyl-5(5(R)- ethyl--hydroxy-6(S)-methyl-2(R)- tetrahydropyranyl)-2(S)-tetrahydrofuryl]heptyl}- salicylic acid can be replaced in this formulation with the same weight of each of the following:

3-rnethyl-6-i7'ethyl-4-hydroxy-3,5-dimethyl-6-oxo- 7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2- tetrahydropyranyl)2-tetra-hydrofuryl]heptyl} acetyl salicylic acid;

5-brom0-3-methyl-6-{7-ethyl-4-hydroxy-3,5- dimethyl-6-oxo-7[5-ethyl-3-methyl-5-(S-ethyl-S- hydroxy-fi-methyl-Z-tetrahydropyranyl)-2- tetrahydrofuryl]heptyl}salicylic acid;

5-chloro-3-methyl-6-{7-ethyl-4-hydroxy-3,5- dimethyl-6-oxo-7-[ 5-ethyl-3-methyl-5-( 5-ethyl 5- hydroxy-6-methyl-Z-tetrahydropyranyl)-2- tetrahydrofuryllheptyl} salicylic acid.

Procedure:

I. The drug was mixed with the lactose, corn starch and pregelatinized corn starch in a suitable size mixer.

2. The mix was passed through a Fitzpatrick Commi' nuting machine fitted with No. 1A screen and with knives forward.

3. The mix was returned to the mixer and moistened with water to a thick paste. The moist mass was passed through a No. 12 screen and the moist granules were dried on paper lined trays at 110F.

4. The dried granules were returned to the mixer, the calcium stearate was added and mixed well.

5. The granules were compressed at a tablet weight of 200 mg. using standard concave punches having a diameter of 5/16 inch.

3-Methyl-6-{7(R)-ethyl-4(S)-hydroxy-3(R),5(S)- dimethyl-6oxo-7-[5(S)-ethyl-3(S)-methyl-5(5(R)- ethyl-5-hydroxy-6(S)-methyl-2(R)- tetrahydropyranyl )-2( S )-tetrahydrofuryl lheptyllsalicylic acid can be replaced in this formulation with the same weight of each of the following:

Example 9 Capsule Formulation 2( R )-tetrahydropyranyl )-2(S l-tetrahydroturyll heptyl}salicylic acid Lactose l58 mg. Corn Starch 37 mg. Talc 5 mg.

2l0 mg.

Procedure:

1. The drug was mixed with the lactose and corn starch in a suitable mixer.

2. The mixture was further blended by passing through a Fitzpatrick Comminuting machine with a No. lA screen with knives forward.

3. The blended power was returned to the mixer, the talc added and blended thoroughly. The mixture was then filled into No. 4 hardshell gelatin capsules on a capsulating machine.

3-Methyl-6-{7(R)-ethyl-4(S)-hydroxy-3(R),5(S)- dimethyl-6-oxo7-[5(S)ethyl-3(S)-methyl-5(5(R)- ethyl-5-hydroxy-6(S)-methyl-2(R)- tetrahydropyranyl)-2(S)-tetrahydrofuryl]heptyl} salicylic acid can be replaced in this formulation with the same weight of each of the following:

3-methyl-6-{7'ethyl-4-hydroxy-3,S-dimethyl--oxo- 7-l5-ethyl-3'methyl-5-(5-ethyl-5-hydroxy-o-methyl-ltetrahydropyranyl)-2-tetrahydrofuryllheptyll acetyl salicylic acid;

5-bromo-3-methyl-6-{7-ethyl-4-hydroxy-3,5- dimethyl-6-oxo-7[5-ethyl-3-methyl-5-( 5-ethyl-5- hydroxy-6-methyl-Z-tetrahydropyranyl)-2- tetrahydrofuryl]heptyl}salicylic acid;

5-chloro-3-methyl-6-{7-ethyl-4-hydroxy-3,5- dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5- hydroxy-6-methyl-Z-tetrahydropyranyl)-2- tetrahydrofuryllheptyllsalicylic acid.

Example 10 Capsule Formulation Procedure:

1. The drug was mixed with lactose and corn starch in a suitable mixer.

2. The mixture was further blended by passing through a Fitzpatrick Comminuting machine with a No. lA screen with knives forward.

3. The blended powder was returned to the mixer, the talc added and blended thoroughly.

4. The mixture was filled into No. 4 hard-shell gelatin capsules on capsulating machine.

3-Methyl-6-{7(R)-ethyl-4(S)-hydroxy-3(R),5(S)- dimethyl-6-oxo-7-[5(S)-ethyl-3(S)-methyl-5(5(R)- ethyl-5-hydroxy-6(S)-methyl-2(R)- tetrahydropyranyl)-2(S)-tetrahydrofuryl]heptyl}- salicylic acid can be replaced in this formulation with the same weight of each of the following:

3-methyl-6-{ 7-ethyl-4-hydroxy-3,S-dimethyl-6-oxo- 7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2- tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}acetyl salicylic acid;

5-brom0-3-methyl-6-{7-ethyl-4-hydroxy-3,5- dimethyl-6-oxo-7[5-ethyl-3-methyl-5-(5-ethyl-5- hydroxy-6-methyl-2-tetrahydropyranyl)-2- tetrahydrofuryl]heptyl}salicylic acid;

5-chloro-3-methyl-6- {7-ethyl-4-hydroxy-3,'5- dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5- hydroxy-fi-methyl-2-tetrahydropyranyl)-2- tetrahydrofuryllheptyl} salicylic acid.

We claim: I

1. A method for improving cardiovascular function in a patient requiring such treatment which comprises administering to such patient an effective amount of a compound represented by the formula I CH3 c2 5 wherein R, is hydrogen or acetyl; R is hydrogen, bromine or chlorine and the pharmaceutically acceptable saltsthereof.

2. The method of claim 1 wherein the compound is 3-methyl-6{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7- [5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2- tetrahydropyranyl)-2-tetrahydrofuryl]heptyl} salicylic acid.

3. The method of claim 1 wherein the compound is 5-bromo-3-methyl 6-{7-ethyl-4-hydroxy-3,S-dimethylwherein R is hydrogen or acetyl; R is hydrogen, bromine or chlorine CH CH C H and the pharmaceutically acceptable salts thereof.

7. The composition of claim 6 wherein the active compound is 3-methyl-6-{7-ethyl-4-hydroxy-3,5- dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5- hydroxy-6-methyl-Z-tetrahydropyranyl)-2- tetrahydrofuryl]heptyl}salicylic acid.

8. The composition of claim 6 wherein the active compound is 5-bromo-3-methyl-6-i7-ethyl-4 hydroxy- 3,5-dimethyl-6-oxo-7-[ 5-ethyl'3-methyl'5-( 5-ethyl-5- hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyllsalicylic acid.

9. The composition of claim 6 wherein the active I compound is 3-methyl-6-{ 7-ethyl-4-hydroxy-3.5-

dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(S-ethyl-S- hydroxy-6-methyl-Z-tetrahydropyranyl)-2- tetrahydrofuryl]heptyllacetyl salicylic acid.

10. The composition of claim 6 wherein the active compound is 5-chloro-3-methyl-6-{7-ethyl-4-hydroxy- 3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(S-ethyl-S hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahy- 65 drofuryl]heptyl}salicylic acid. 

1. A METHOD FOR IMPROVING CARDIOVASCULAR FUNCTION IN A PATIENT REQUIRING SUCH TREATMENT WHICH COMPRISES ADMINISTERING TO SUCH PATIENT AN EFFECTIVE AMOUNT OF A COMPOUND REPRESENTED BY THE FORMULA
 2. The method of claim 1 wherein the compound is 3-methyl-6(7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-(5-ethyl-3-methyl-5-(5 -ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2 -tetrahydrofuryl)heptyl)salicylic acid.
 3. The method of claim 1 wherein the compound is 5-bromo-3-methyl-6-(7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-(5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2 -tetrahydrofuryl)heptyl)salicylic acid.
 4. The method of claim 1 wherein the compound is 3-methyl-6-(7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-(5-ethyl-3-methyl-5-(5 -ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2 -tetrahydrofuryl)heptyl)acetyl salicylic acid.
 5. The method of claim 1 wherein the compound is 5-chloro-3-methyl-6-(7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-(5-ethyl-3 -methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2 -tetrahydrofuryl)heptyl) salicylic acid.
 6. A parenteral composition for producing myocardial stimulation in patients requiring such effects comprising an inert non-toxic pharmaceutically acceptable parenteral vehicle and an effective amount of an active compound in solution represented by the formula
 7. The composition of claim 6 wherein the active compound is 3-methyl-6-(7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-(5-ethyl-3-methyl-5-(5 -ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2 -tetrahydrofuryl)heptyl)salicylic acid.
 8. The composition of claim 6 wherein the active compound is 5-bromo-3-methyl-6-(7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-(5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2 -tetrahydrofuryl)heptyl) salicylic acid.
 9. The composition of claim 6 wherein the active compound is 3-methyl-6-(7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-(5-ethyl-3-methyl-5-(5 -ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2 -tetrahydrofuryl)heptyl)acetyl salicylic acid.
 10. The composition of claim 6 wherein the active compound is 5-chloro-3-methyl-6-(7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-(5-ethyl-3 -methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2 -tetrahydrofuryl)heptyl) salicylic acid. 